rs373428732

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_000038.6(APC):​c.2627G>A​(p.Arg876Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000601 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R876G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

1
11
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:2

Conservation

PhyloP100: 5.55
Variant links:
Genes affected
APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.37479278).
BP6
Variant 5-112838221-G-A is Benign according to our data. Variant chr5-112838221-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221081.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=10, Benign=1}.
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APCNM_000038.6 linkuse as main transcriptc.2627G>A p.Arg876Gln missense_variant 16/16 ENST00000257430.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APCENST00000257430.9 linkuse as main transcriptc.2627G>A p.Arg876Gln missense_variant 16/165 NM_000038.6 P1P25054-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152098
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000518
AC:
13
AN:
250804
Hom.:
0
AF XY:
0.0000738
AC XY:
10
AN XY:
135534
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000795
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000629
AC:
92
AN:
1461884
Hom.:
0
Cov.:
33
AF XY:
0.0000688
AC XY:
50
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000692
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152098
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.0000529
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000576
AC:
7
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 11, 2024In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with papillary renal cell carcinoma and in an individual with breast cancer (PMID: 29684080, 35264596); This variant is associated with the following publications: (PMID: 21901162, 24142997, 22895193, 35264596, 27930734, 36243179, 35534704, 29684080) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJun 05, 2023In the published literature, this variant has been reported in individual with breast cancer (PMID: 35264596 (2022)) and myelodysplastic syndrome (PMID: 24142997 (2013)). The frequency of this variant in the general population, 0.00014 (7/50496 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Familial adenomatous polyposis 1 Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Feb 15, 2023This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 21, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylSep 13, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsJul 02, 2018- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 30, 2023This missense variant replaces arginine with glutamine at codon 876 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with kidney cancer (PMID: 29684080). This variant has been identified in 15/282206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsAug 03, 2020This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 11, 2023Variant summary: APC c.2627G>A (p.Arg876Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250804 control chromosomes, predominantly at a frequency of 8e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2627G>A has been reported in the literature in an individual(s) affected with breast cancer without strong evidence of causality (e.g. Guindalini_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27930734, 35264596, 35534704). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7), likely benign (n=1) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Classic or attenuated familial adenomatous polyposis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 01, 2023This missense variant replaces arginine with glutamine at codon 876 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with kidney cancer (PMID: 29684080). This variant has been identified in 15/282206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.079
D
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
.;D;D;D
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D;.;D;D
M_CAP
Benign
0.042
D
MetaRNN
Benign
0.37
T;T;T;T
MetaSVM
Uncertain
0.57
D
MutationAssessor
Uncertain
2.3
.;M;M;.
MutationTaster
Benign
0.98
D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.67
N;N;N;N
REVEL
Uncertain
0.47
Sift
Benign
0.23
T;T;T;T
Sift4G
Benign
0.62
T;T;T;T
Polyphen
0.97
.;D;D;.
Vest4
0.68, 0.72
MVP
0.87
ClinPred
0.11
T
GERP RS
5.9
Varity_R
0.14
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs373428732; hg19: chr5-112173918; COSMIC: COSV57362834; COSMIC: COSV57362834; API